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Abstract

  1. Top of page
  2. Abstract
  3. The Physiology of Water Handling and Arginine Vasopressin
  4. The Pathologic Role of Vasopressin in HF
  5. Hyponatremia in HF
  6. Diuretic-Induced Hyponatremia
  7. AVP Antagonists for the Therapy of Hyponatremia and HF
  8. V2-Receptor Antagonists
  9. V1a-/V2-Receptor Antagonists
  10. Conclusions
  11. Acknowledgments
  12. References

Congest Heart Fail. 2010;16(4)(suppl 1):S7–S14. ©2010 Wiley Periodicals, Inc.

Heart failure (HF) is associated with substantial cost, morbidity, and mortality. One of the common complications associated with HF, as well as with its treatment, is the development of hyponatremia. Hyponatremia is due to the nonosmotic release of arginine vasopressin (AVP) along with neurohormonal activation of the renin-angiotensin-aldosterone and sympathetic nervous systems. Hyponatremia in patients with HF is associated with poor outcomes and can limit the use of diuretic therapy. Given that AVP is the primary stimulus for the development of hyponatremia in these patients, therapies that target AVP action would seem a logical choice in the therapeutic regimen for HF. Drugs that antagonize the action of AVP at the vasopressin V2 receptor, which is primarily responsible for water resorption in the kidney, are now available and have been studied in patients with HF. These drugs (termed vaptans) have been associated with improvements in serum sodium concentration, urine output, body weight, and mental functioning but have shown no long-term mortality benefit in patients with HF. The role of vaptans in the HF armament will require further studies that center on the proper timing and indications for their use as well as their cost-efficacy.

Heart failure (HF) affects more than 5 million patients in the United States, with an incidence of 10 in 1000 in those older than 65.1 HF is associated with significant morbidity and mortality rates that continue to grow despite advances in care: hospital discharges for HF rose from 399,000 in 1979 to 1,099,000 in 2004, and deaths from HF increased 28%.1 In fact, in 2004, 1 in 8 death certificates in the United States mentioned HF as a contributing cause.1 Given this burden, there is clearly an unmet need for safe and effective strategies to treat HF.

Intimately associated with HF and its treatment with diuretic agents is the development of hyponatremia.2 Hyponatremia (serum sodium concentration [Na+] <134 mmol/L) occurs in more than 20% of patients hospitalized for HF and is an independent predictor of poor outcomes.3,4 As discussed in this article, the development of hyponatremia in patients with HF is secondary to both neurohormonal and renal mechanisms that are operative in patients with impaired cardiac function.3,4 Furthermore, the injudicious use of diuretics may further activate these maladaptive mechanisms and worsen the development of hyponatremia.

Recently, the development of drugs that specifically antagonize vasopressin action at the level of the vasopressin receptor (aquaretic agents) has led to the potential to treat the volume overload that accompanies HF by directly antagonizing a pathogenic pathway. Concomitant with the use of these agents is the ability to treat hyponatremia associated with HF through the selective increase in renal free water excretion.5

The Physiology of Water Handling and Arginine Vasopressin

  1. Top of page
  2. Abstract
  3. The Physiology of Water Handling and Arginine Vasopressin
  4. The Pathologic Role of Vasopressin in HF
  5. Hyponatremia in HF
  6. Diuretic-Induced Hyponatremia
  7. AVP Antagonists for the Therapy of Hyponatremia and HF
  8. V2-Receptor Antagonists
  9. V1a-/V2-Receptor Antagonists
  10. Conclusions
  11. Acknowledgments
  12. References

HF is associated with the progressive development of neurohormonal abnormalities that can lead to the typical symptoms of dyspnea, orthopnea, exercise intolerance, and fatigue. The important role of the sympathetic nervous system (SNS) and renin-angiotensin-aldosterone system (RAAS) has been elucidated, and inhibition of these systems with β-blockers, angiotensin-converting enzyme inhibitors, and angiotensin receptor blockers is central to the care of patients with HF and has been shown to lead to significant improvement in outcomes.6 There are additional neurohormonal pathways that are activated and play an important role in the pathophysiology and symptomatology of HF and serve as potential targets for pharmacologic therapy. One prime example is arginine vasopressin (AVP).7

AVP is a nonapeptide hormone synthesized in the hypothalamus and stored and released from the posterior pituitary.8 The primary function of AVP is to control water excretion in the kidney and regulate vascular tone by acting through the V2 and V1a receptors, respectively. AVP has additional, diverse roles in the physiology of numerous other systems (Table I).

Table I.   Arginine Vasopressin Actions: Receptors, Localization, and Function
ReceptorLocationFunction
V1aVascular smooth muscleVasoconstriction
Myocardial hypertrophy
PlateletsAggregation
MyometriumUterine contraction
V1b (V3)Anterior pituitaryAdrenocorticotropin hormone release
β-Endorphin release
V2Renal collecting tubuleFree water resorption
Induction of aquaporin-2
Vascular endotheliumRelease of von Willebrand factor
Release of factor VIII

Osmotic and nonosmotic stimulation are the 2 major factors that control AVP release. Osmoreceptors reside in the hypothalamus and are exceedingly sensitive to changes in plasma osmolality (±1% to 2%). Indeed, AVP-releasing neurons in the supraoptic nucleus of the hypothalamus are directly osmosensitive, and this osmosensitivity is mediated by stretch-inhibited cation channels that are variants of the transient receptor potential vanilloid type-1 family.9 There is a close correlation between plasma osmolality and plasma AVP levels, and the osmotic threshold for AVP secretion is set at approximately 280 mOsm/kg.10 The osmotic threshold is also modulated by nonosmotic stimuli. A fall in blood volume, cardiac output, or blood pressure enhances the secretion of AVP for any given osmotic stimulus (effectively shifting the dose [plasma osmolality] vs AVP release relationship to the left).11 The effects of changes in blood volume, cardiac output, and blood pressure on AVP secretion are mediated through the high- (aortic arch, carotid sinus) and low-pressure (left atrial) baroreceptors.12 While in normal physiologic states, the effects of changes in plasma osmolality generally take precedence over changes in volume in controlling AVP release, in pathophysiologic states, the nonosmotic release of AVP might override the effect of hypo-osmolality to normally suppress AVP release.8 Such is the case in patients with HF, in whom the nonosmotic release of AVP is common. Furthermore, recent studies have demonstrated that in patients with HF, there is a significant increase in the relative density (by 30%) of AVP-positive neurons in the supraoptic nucleus, likely reflecting the chronic stimulation of AVP production through persistent effective circulating volume depletion.13

After its release into the circulation, AVP binds to V2 receptors on the basolateral cells of the renal collecting duct.14 This binding stimulates the synthesis and apical transport of aquaporin-2, a water channel that increases collecting duct water permeability and reabsorption of free water via a hypertonic renal medullary osmotic gradient.15 The net result is return of water to the circulation, dilution of the plasma volume, and production of concentrated, low-volume urine. In the absence of AVP, the collecting duct remains impermeable to water and dilute, large-volume urine is produced.

In addition to its renal effects, AVP also regulates vascular tone via V1A receptors located on vascular smooth muscle cells, resulting in potent arteriolar vasoconstriction.16 AVP acting through the V1a receptor may also mediate cardiomyocyte growth and hypertrophy.16

The Pathologic Role of Vasopressin in HF

  1. Top of page
  2. Abstract
  3. The Physiology of Water Handling and Arginine Vasopressin
  4. The Pathologic Role of Vasopressin in HF
  5. Hyponatremia in HF
  6. Diuretic-Induced Hyponatremia
  7. AVP Antagonists for the Therapy of Hyponatremia and HF
  8. V2-Receptor Antagonists
  9. V1a-/V2-Receptor Antagonists
  10. Conclusions
  11. Acknowledgments
  12. References

In several animal models of HF and in patients with congestive HF, significant increases in AVP levels have been consistently demonstrated.17–19 Data from the Studies of Left Ventricular Dysfunction (SOLVD) show a progressive incremental increase in AVP levels as congestive symptoms worsen.19 The Survival and Ventricular Enlargement trial showed that high AVP levels are associated with worsened 1-year cardiovascular mortality rates.20 Furthermore, the use of afterload-reducing agents (angiotensin-converting enzyme inhibitors) led to improved water excretion and suppressed AVP levels in response to a water load.21 These results suggest that a decrease in stroke volume and cardiac output (as sensed by the arterial baroreceptors in the carotid sinus and aortic arch or via other mechanisms) is the primary stimulus for AVP release and that this release is nonosmotically controlled (arterial underfilling)22,23 (Figure 1). Critically important is that despite slightly lower plasma osmolality, AVP levels are increased in patients with HF, consistent with a primary nonosmotic release mechanism.

image

Figure 1.  Arginine vasopressin (AVP) release in heart failure. In a normal heart, an increase in atrial pressure blocks the release of AVP through the Henry-Gauer reflex. Increases in atrial pressure cause a parallel release of atrial natriuretic peptide, with consequent increase in urinary sodium and water excretion. These mechanisms are designed to maintain volume, pressure, and organ perfusion within normal ranges. In a failing heart, AVP is released from the pituitary gland due in response to arterial underfilling. Stimulation of V1a receptors of the vasculature leads to increased vascular resistance, while stimulation of the V2 receptors in the collecting duct leads to an increase in water reabsorption and dilutional hyponatremia. AVP also increases urea transport in collecting ducts of the nephron, leading to increased urea levels in blood and possible discrepancies between creatinine and blood urea nitrogen levels. RAA indicates renin-angiotensin-aldosterone; BNP, B-type natriuretic peptide.

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Mechanistically, the increase in nonosmotically released AVP may be through HF-mediated activation of the SNS and RAAS. The SNS, reacting to stimulation of baroreceptor reflexes or via other mechanisms, stimulates the supraoptic and paraventricular nuclei in the hypothalamus to synthesize and release AVP. The same is true for activation of the RAAS.23,24 In fact, Lilly and associates25 showed that hyponatremic patients had significantly increased plasma renin activity and norepinephrine and epinephrine levels compared with patients with normal serum sodium levels. Along those lines, hyonatremic patients had a significantly better outcome when treated with angiotensin-converting enzyme inhibitors than when treated with vasodilators (median survival, 232 vs 108 days).26

In concert with other neurohormonal systems that are activated in HF, elevated AVP levels contribute to abnormal hemodynamics by increasing systemic vascular resistance, afterload, and pulmonary capillary wedge pressure.23,24 Furthermore, prolonged exposure to high levels of AVP may contribute to vascular smooth muscle cell hypertrophy and hyperplasia as well as myocardial hypertrophy and adverse cardiac remodeling.27 Excess AVP is also critically important in the pathogenesis of impaired free water excretion, which commonly complicates HF.19 Impaired free water excretion has important implications: (1) it worsens volume expansion and congestive symptoms; (2) it contributes to a higher incidence of hypo-osmolar hyponatremia through promotion of continued negative free water balance; and (3) it increases the risk of hyponatremia when diuretic therapy is instituted for the treatment of congestive symptoms.

Hyponatremia in HF

  1. Top of page
  2. Abstract
  3. The Physiology of Water Handling and Arginine Vasopressin
  4. The Pathologic Role of Vasopressin in HF
  5. Hyponatremia in HF
  6. Diuretic-Induced Hyponatremia
  7. AVP Antagonists for the Therapy of Hyponatremia and HF
  8. V2-Receptor Antagonists
  9. V1a-/V2-Receptor Antagonists
  10. Conclusions
  11. Acknowledgments
  12. References

One consequence of the nonosmotically mediated increase in AVP levels in patients with HF is the development of hyponatremia. Dilutional hyponatremia occurs secondary to the persistent activation of renal water reabsorption despite a low plasma osmolality that would normally suppress AVP release. In the presence of continued fluid intake, the presence of AVP leads to continued water absorption and dilution of the plasma volume. The water-retaining effect of AVP is exacerbated by the RAAS and SNS, which act to further limit water excretion by lowering glomerular filtration rate and increasing proximal water and sodium reabsorption. The net effect is limitation of delivery of plasma filtrate to the diluting segments of the nephron with limitation of water excretion.

Of those patients admitted to the hospital with HF, at least 18% to 27% are found to have serum Na+ levels <135 mmol/L at admission.28,29 Importantly, hyponatremia is a strong marker for adverse outcomes. Lee and Packer30 analyzed 30 clinical, hemodynamic, and biochemical variables and their association with survival in 203 consecutive patients with severe HF. The most powerful predictor of cardiovascular mortality was pretreatment serum Na+, with hyponatremic patients having a substantially shorter median survival than patients with a normal serum Na+ (164 vs 373 days, P=.006). In the Outcomes of a Prospective Trial of Intravenous Milrinone for Exacerbations of Chronic Heart Failure (OPTIME-CHF) study, both in-hospital and 60-day mortality rates were highest for patients with the lowest admission serum Na+ levels.28 In the Organized Program to Initiate Lifesaving Treatment in Hospitalized Patients With Heart Failure (OPTIMIZE-HF) registry, patients with hyponatremia had significantly higher in-hospital and follow-up mortality rates and longer hospital stays.31 In this study, for each 3-mmol/L decrease in serum Na+ <140 mmol/L at admission, the risk of in-hospital mortality and follow-up mortality increased by 19.5% and 10%, respectively.31 Recently, the importance of persistent hyponatremia in HF patients was described in a cohort of patients enrolled in the Evaluation Study of Congestive Heart Failure and Pulmonary Artery Catheterization Effectiveness (ESCAPE).32 Hyponatremia was associated with higher 6-month mortality after covariate adjustment (hazard ratio [HR] for each 3-mEq/L decrease in sodium level, 1.23; 95% confidence interval [CI], 1.05–1.43; P=.01). After controlling for baseline variables and clinical response, patients with persistent hyponatremia had an increased risk of all-cause mortality (31% vs 16%; HR, 1.82; P=.04), HF rehospitalization (62% vs 43%; HR, 1.52; P=.03), and death or rehospitalization (73% vs 50%; HR, 1.54; P=.01) compared with normonatremic patients.

The mechanistic link between hyponatremia and mortality risk is not clear. It is clear that hyponatremia likely reflects more severe activation of the RAAS and the SNS and higher AVP levels that correlate with more severe HF.33,34 Furthermore, the development of hyponatremia itself may have important implications for limiting certain therapeutic options such as continued diuretic use. Dissecting the mechanisms involved in the contribution of hyponatremia to poor outcomes requires further study.

Diuretic-Induced Hyponatremia

  1. Top of page
  2. Abstract
  3. The Physiology of Water Handling and Arginine Vasopressin
  4. The Pathologic Role of Vasopressin in HF
  5. Hyponatremia in HF
  6. Diuretic-Induced Hyponatremia
  7. AVP Antagonists for the Therapy of Hyponatremia and HF
  8. V2-Receptor Antagonists
  9. V1a-/V2-Receptor Antagonists
  10. Conclusions
  11. Acknowledgments
  12. References

Diuretic therapy (mostly with loop-type diuretic agents) is a mainstay of pharmacologic therapy for HF. In recent large-scale trials, 85% to 100% of symptomatic patients and 16% to 35% of asymptomatic patients with reduced left ventricular function received either a loop-type or thiazide diuretic.34,35 Despite their widespread use and efficacy in improving congestive symptoms, diuretic compounds have not shown improved survival in patients with HF.36 In part, the lack of demonstrable long-term benefit from diuretic therapy may be attributable to numerous metabolic complications, such as hypokalemia, acid-base disturbances, hypomagnesemia, hyperuricemia, lipid disorders, glucose intolerance, and hyponatremia, that result from the use of these drugs.37 Furthermore, diuretic use leads to a series of neurohormonal consequences, such as activation of the RAAS and SNS and release of AVP.38,39

Diuretics play an important role in the development and worsening of hyponatremia in patients with HF. In an analysis of 129 cases of severe hyponatremia, diuretics were deemed responsible in 94% of cases.40 Several European studies also demonstrated a high incidence of diuretic use in patients with hyponatremia.41 Most cases of diuretic-induced hyponatremia are caused by thiazide diuretics, with loop diuretics being implicated less commonly.40,41 For example, in the above study, thiazide diuretics were responsible for 63% of hyponatremia cases, while loop diuretics were responsible for only 6% of cases.40

The mechanism of diuretic-induced hyponatremia involves 3 main features: (1) impairment of the kidney’s capability to reabsorb solute in the absence of water (diluting mechanism); (2) diminution of glomerular filtration rate due to volume depletion; and perhaps most importantly, (3) stimulation of further AVP secretion due to effective circulating volume depletion (Figure 2).42 Furthermore, as discussed above, HF itself is associated with impaired urinary diluting capacity as well as high AVP levels due to effective circulating volume depletion. This underlying condition likely increases the risk of diuretic-induced hyponatremia through progressive AVP release and a dose-dependent increase in urinary concentration. Thus, while diuretics are effective in improving congestive symptoms, they are associated with progressive hyponatremia that can limit their use and mandates other strategies for both therapy of congestive symptoms as well as the dilutional hyponatremia.

image

Figure 2.  Effect of tolvaptan, placebo, and furosemide on (A) urinary sodium, (B) urine osmolality, (C) urine volume (flow rate), and (D) renal blood flow. Bars represent weighted averages during an observation period of 9 hours. *P<.05. Adapted from Costello-Boerrigter and colleagues. 46

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AVP Antagonists for the Therapy of Hyponatremia and HF

  1. Top of page
  2. Abstract
  3. The Physiology of Water Handling and Arginine Vasopressin
  4. The Pathologic Role of Vasopressin in HF
  5. Hyponatremia in HF
  6. Diuretic-Induced Hyponatremia
  7. AVP Antagonists for the Therapy of Hyponatremia and HF
  8. V2-Receptor Antagonists
  9. V1a-/V2-Receptor Antagonists
  10. Conclusions
  11. Acknowledgments
  12. References

Given the primary role AVP has in causing congestive symptoms, free water retention, and ultimately hyponatremia (as well as the worsening of hyponatremia associated with diuretic use), therapy targeting AVP action would seem to be a rational approach to therapy for HF. This therapy would lead to a selective increase in free water excretion by the kidney, termed aquaresis.

Nonpeptide AVP antagonists that target either the V2 receptor or a combination of the V2 and V1a receptors resulting in aquaresis are now available. The pharmacologic effects of a selective group of these antagonists are shown in Table II. Clinical trials studying these agents have focused on 2 populations: patients with hyponatremia due to various causes, such as HF, cirrhosis, or the syndrome of inappropriate antidiuretic hormone secretion, and those with either stable or decompensated HF (many of whom did not have baseline hyponatremia).

Table II.   Nonpeptide Arginine Vasopressin Receptor Antagonists
 ConivaptanLixivaptanTolvaptan
Receptor antagonismV1a/V2V2V2
Route of administrationIntravenousOralOral
Urine volumeIncreaseIncreaseIncrease
Urine osmolalityDecreaseDecreaseDecrease
Sodium excretionNo changeMay be increased with higher dosesNo change
MetabolismHepatic (CYP3A4/D6)Hepatic (CYP3A4)Hepatic (CYP3A4)

V2-Receptor Antagonists

  1. Top of page
  2. Abstract
  3. The Physiology of Water Handling and Arginine Vasopressin
  4. The Pathologic Role of Vasopressin in HF
  5. Hyponatremia in HF
  6. Diuretic-Induced Hyponatremia
  7. AVP Antagonists for the Therapy of Hyponatremia and HF
  8. V2-Receptor Antagonists
  9. V1a-/V2-Receptor Antagonists
  10. Conclusions
  11. Acknowledgments
  12. References

Administration of a V2-receptor antagonist leads to an increase in free water excretion, little or no sodium loss, and importantly, no compensatory activation of the RAAS.43–45 In an open-label, single-dose, placebo-controlled crossover study in 14 patients with New York Heart Association (NYHA) class II or III HF, tolvaptan 30 mg was compared with furosemide 80 mg. Tolvaptan and furosemide induced a similar diuresis and reduced urine osmolality. However, tolvaptan, unlike furosemide, did not increase urinary sodium or potassium excretion or reduce renal blood flow (Figure 2).46 No differences were observed regarding effects on plasma AVP, mean arterial pressure, or glomerular filtration rate. These encouraging preclinical results led to a series of clinical trials in patients with HF using the V2-receptor antagonist tolvaptan. Tolvaptan is 29 times more selective for the V2 receptor than for the V1a receptor, and the induced aquaresis with tolvaptan occurs in the first 6 to 8 hours after drug administration.47

The first of these studies was a double-blind placebo-controlled study of 254 patients with HF (NYHA class II or III) who received either 1 of 3 oral doses of tolvaptan (30, 45, or 60 mg/d) or placebo for 25 days.48 All patients were treated as outpatients, did not receive fluid restriction, and continued standard HF therapies. All 3 doses of tolvaptan were associated with significant reductions in body weight that were maintained throughout the study (however, the body weight reduction was largely due to fluid loss at initiation of therapy). All doses of tolvaptan increased urine output and improved clinical signs and symptoms of HF. In addition, all tolvaptan doses produced small mean increases in serum Na+ levels. At baseline, 28% of patients were hyponatremic and had the greatest overall rise in serum Na+ levels. Normalization of hyponatremia occurred on day 1 in 80% of patients who received tolvaptan compared with 40% of those who received placebo. Major adverse effects included polyuria, thirst, and dry mouth. There were no changes from baseline in serum electrolyte levels, blood pressure, or renal function.

Based on these encouraging results, a second randomized, multicenter, placebo-controlled trial in patients hospitalized for an acute exacerbation of HF (Acute and Chronic Therapeutic Impact of a Vasopressin Antagonist in Congestive Heart Failure [ACTIV in CHF]) was performed.29 In this study, 319 patients were randomized to 1 of 3 tolvaptan dosages (30, 60, or 90 mg/d) or placebo for 60 days, in addition to standard HF therapy. Median body weight at 24 hours postrandomization decreased significantly in the groups given tolvaptan (in the highest-dose group, the median decrease in weight was 2.05 kg). At baseline, 21.3% of patients were hyponatremic. Patients in the tolvaptan group also had small increases in serum Na+ that were greater in those with baseline hyponatremia. The decrease in body weight was not associated with changes in heart rate, blood pressure, renal function, or development of hypokalemia. After 60 days, there was no significant difference in the primary end points of death, hospitalization, and worsening HF; however, a trend toward decreasing mortality was seen in the tolvaptan group (P=.18).

Short- and long-term end points among 4133 patients being admitted for acute decompensated HF were evaluated in the Efficacy of Vasopressin Antagonism in Heart Failure Outcome Study With Tolvaptan (EVEREST) program. It comprised 3 trials: 2 identical short-terms trials (clinical status trials) that compared tolvaptan with placebo on the seventh day or discharge and a single long-term outcomes study that followed patients for at least 60 days. It is important to realize that the majority of patients in this study did not have baseline hyponatremia. Patients were randomized to tolvaptan 30 mg/d in addition to standard care or to placebo plus standard care.49,50 The short-term trials focused on a composite of patient-assessed global clinical features and body weight that was assessed at day 7 after starting therapy. While the scores in global clinical status between groups did not differ, there was a significant reduction in body weight in the tolvaptan group accompanied by modest improvements in dyspnea. The degree of weight loss at day 1 (1.7–1.8 vs 1.0 kg with placebo plus standard therapy) and at day 7 or discharge (3.3–3.8 kg vs 2.7–2.8 kg with placebo plus standard therapy) were statistically in favor of tolvaptan. In the long-term follow-up trial (over a mean of 9.9 months), there was no difference in the end points of all-cause mortality, cardiovascular death, or HF hospitalization between the groups. However, those taking tolvaptan had reductions in body weight and improved serum Na+ with modest improvements in signs and symptoms of HF and no excess adverse events. Compared wtih baseline, furosemide dosage at discharge was reduced more in the tolvaptan-treated patients.

In a subgroup analysis of EVEREST, approximately 8% of patients had hyponatremia.49 In these patients, serum Na+ increased by 5.5 and 1.8 mEq/L in the tolvaptan and placebo groups, respectively. However, just as in the larger cohort, there was no associated decrease in mortality with tolvaptan in this subgroup. Recently, the hemodynamic effects of tolvaptan in patients with HF were studied.51 In patients with advanced HF, a single dose of tolvaptan (15, 30, or 60 mg) resulted in modest changes in cardiac filling pressures and significant increase in urine output. None of the other secondary outcome measures, including cardiac output, cardiac index, systemic vascular resistance, heart rate, and blood pressure, showed significant changes with tolvaptan. These data provide mechanistic support for the favorable effects of tolvaptan in patients with decompensated HF.51

Lixivaptan, another highly specific V2-receptor antagonist, has been studied in patients with stable HF.52 Forty-two diuretic-dependent patients with mild to moderate HF (NYHA class II or III HF) were randomized in a double-blind, placebo-controlled, ascending (10–400 mg) single-dose study. As with tolvaptan, dose-dependent increases in urine output (from 1.8 L with placebo up to 3.9 L with the 400-mg lixivaptan dose), solute-free water clearance, and serum Na+ were demonstrated, but no long-term outcome studies with this agent have been published. The Treatment of Hyponatremia Based on Lixivaptan in NYHA Class III/IV Cardiac Patient Evaluation (BALANCE) is an ongoing multicenter, international, randomized, double-blind study of the effects of titrated oral lixivaptan in patients with hyponatremia hospitalized for HF. The study will include approximately 650 patients who will receive lixivaptan or placebo with dose titration for 60 days. The primary objective of the study is to determine whether lixivaptan can effectively and safely increase serum Na+ in patients with HF with hyponatremia and volume overload. Secondary objectives include an assessment of all-cause mortality, cardiovascular effects, HF hospitalization, and acute change in body weight.53

Because we lack long-term mortality benefit, the exact role of these agents in the treatment of HF and hyponatremia is unclear. However, these agents have been shown to improve symptoms without an adverse effect profile and thus may have a role in improving quality of life. In the Study of Ascending Levels of Tolvaptan in Hyponatremia (SALT)-1 and SALT-2 trials, the effects of tolvaptan on serum Na+ in patients with either euvolemic or hypervolemic hyponatremia due to the syndrome of inappropriate antidiuretic hormone secretion, HF, or cirrhosis were studied.54 Patients administered tolvaptan had significant increases in serum Na+, and these were associated with a favorable effect on the mental component summary of the Short Form-12 health survey. Thus, despite having no mortality benefit, these agents may have a role in improving symptoms associated with HF.

Preliminary data from a single study do suggest that vasopressin-receptor antagonism in patients with HF on once-daily furosemide may allow for reduction or even discontinuation of loop diuretics in some cases.55 This finding will need further evaluation in larger, long-term studies.

V1a-/V2-Receptor Antagonists

  1. Top of page
  2. Abstract
  3. The Physiology of Water Handling and Arginine Vasopressin
  4. The Pathologic Role of Vasopressin in HF
  5. Hyponatremia in HF
  6. Diuretic-Induced Hyponatremia
  7. AVP Antagonists for the Therapy of Hyponatremia and HF
  8. V2-Receptor Antagonists
  9. V1a-/V2-Receptor Antagonists
  10. Conclusions
  11. Acknowledgments
  12. References

Conivaptan is a nonpeptide, intravenous, V1a-/V2-receptor antagonist (10:1 selectivity) that is approved by the US Food and Drug Administration for the treatment of euvolemic and hypervolemic hyponatremia. Given the fact that conivaptan antagonizes the vascular effects of AVP, it was hypothesized that this agent would reduce afterload and further improve HF symptoms. In fact, in a dog model, intravenous conivaptan inhibits the pressor response seen when exogenous vasopressin was administered.56 Approval of conivaptan was based on a double-blind, placebo-controlled, randomized, multicenter study that enrolled 84 hospitalized patients with euvolemic or hypervolemic hyponatremia. Patients received either 1 of 2 doses of conivaptan (40 or 80 mg/d) or placebo, in addition to current standard-of-care treatment (including fluid restriction). Trial data indicated that the 40-mg/d dosage produced an increase in serum Na+ of at least 4 mEq/L in 23.7 hours and a 6-mEq/L increase or normalization (≥135-mEq/L) in 69% of patients after 4 days.57

Published studies in patients with HF treated with conivaptan are limited. In an early study, 142 patients with symptomatic HF (NYHA class III or IV) received a single intravenous dose of conivaptan (10, 20, or 40 mg) or placebo.58 Compared with placebo, conivaptan led to a dose-dependent fall in pulmonary capillary wedge pressure (−5.4±0.7 mm Hg at the 20-mg dose and −4.6±0.7 mm Hg at the 40-mg dose vs −2.6 ± 0.7 mm Hg for placebo) and right atrial pressure, along with a significant increase in urine output. During this study, there was no change in cardiac index, systemic/pulmonary vascular resistance, blood pressure, or heart rate in those who received conivaptan.

These results were extended in a pilot, double-blind, multicenter trial of 170 patients with decompensated HF receiving standard therapy. In this trial, conivaptan (20-mg loading dose, followed by a continuous infusion of 40, 80, or 120 mg/d for 2 days) significantly increased urine output (on average, 1–1.5 L) compared with placebo, was hemodynamically well-tolerated, and had minimal adverse effects. However, in this trial, there was no change in respiratory symptoms.59 One hundred thirty-five patients in this trial received conivaptan or placebo along with furosemide.60 Unlike the administration of furosemide alone, the addition of conivaptan elicited a dose-dependent increase in urine output (approximately 1 L additional urine output per day). Furthermore, serum Na+ tended to fall in the furosemide-only group, while there was a modest (approximately 2–3 mEq/L) rise in serum Na+ in the group given conivaptan concomitantly. At this time, the role of combined V1a-/V2-receptor antagonists in the therapy of HF remains undefined.61,62 An important issue is that conivaptan has numerous cytochrome P450 interactions with other cardiovascular medications, which makes it impractical for oral long-term use; thus, only an intravenous formulation is available for short-term use.

Conclusions

  1. Top of page
  2. Abstract
  3. The Physiology of Water Handling and Arginine Vasopressin
  4. The Pathologic Role of Vasopressin in HF
  5. Hyponatremia in HF
  6. Diuretic-Induced Hyponatremia
  7. AVP Antagonists for the Therapy of Hyponatremia and HF
  8. V2-Receptor Antagonists
  9. V1a-/V2-Receptor Antagonists
  10. Conclusions
  11. Acknowledgments
  12. References

Vasopressin plays a key pathogenic role in HF. This knowledge has led to the rational approach of AVP antagonism as a method of treating both the congestive symptoms as well as the electrolyte (specifically, hyponatremia) abnormalities associated with HF. Clinical trials with several AVP receptor antagonists (termed vaptans) have promising early results in improving dyspnea, increasing urine volumes, and improving hyponatremia. Further studies are needed to clearly delineate the role of vaptans in the HF armament. Key clinical questions will center around issues such as the timing of and indications for vaptan initiation, duration of therapy, and combination therapy with other HF drugs. Larger and longer-duration clinical trials will be needed to demonstrate the effects of vaptans on outcomes measures such as mortality and hospital admissions.

Acknowledgments

  1. Top of page
  2. Abstract
  3. The Physiology of Water Handling and Arginine Vasopressin
  4. The Pathologic Role of Vasopressin in HF
  5. Hyponatremia in HF
  6. Diuretic-Induced Hyponatremia
  7. AVP Antagonists for the Therapy of Hyponatremia and HF
  8. V2-Receptor Antagonists
  9. V1a-/V2-Receptor Antagonists
  10. Conclusions
  11. Acknowledgments
  12. References

Disclosures:  Dr Rosner received an honorarium funded by educational grants from Otsuka Pharmaceutical and Abbott Laboratories for time and expertise spent in writing this article and has no other financial interests to report. Dr Ronco has received past honoraria from Gambro and Inverness Medical and has served as a speaker for Abbott Laboratories.

References

  1. Top of page
  2. Abstract
  3. The Physiology of Water Handling and Arginine Vasopressin
  4. The Pathologic Role of Vasopressin in HF
  5. Hyponatremia in HF
  6. Diuretic-Induced Hyponatremia
  7. AVP Antagonists for the Therapy of Hyponatremia and HF
  8. V2-Receptor Antagonists
  9. V1a-/V2-Receptor Antagonists
  10. Conclusions
  11. Acknowledgments
  12. References
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